Grant: Operating Grant

Focal segmental glomerulosclerosis (FSGS) is in incurable progressive kidney disease that often necessitates kidney transplantation. This disease affects specialized kidney cells (podocytes) which normally work to prevent passage of proteins from blood into the urine. Unfortunately, in about one third of FSGS patients, FSGS recurs within hours of transplantation. This strongly suggests that the disease is caused by a toxic blood factor which damages podocytes. Patients with recurrent FSGS are destined for a life-long dialyses, and their lives are shortened dramatically. We developed novel techniques to study the effects of patient's blood on podocytes. By applying these new methods, we discovered that the toxic blood factor activates TNF-alpha signaling pathway that drives pathogenesis of recurrent FSGS in some patients. In this project we will study the mechanism by which TNF-alpha affects podocytes. We will use a few approaches: 1) With the help of our colleagues from USA, Canada and France, we will amass a large collection of blood samples from the FSGS patients and will ascertain by using our novel functional and quantitative podocyte assays what proportion of FSGS cases may may be responsive to TNF-alpha blockade. 2) In the podocyte cultures, we will study the effects of TNF-alpha on cell adhesion and cell-cell contacts and other cellular and molecular mechanisms. 3) To test our hypothesis that inappropriate activation of TNF-alpha signalling in podocytes drives the disease, we will generate a transgenic mouse model to test whether a local podocyte expression of TNF-alpha will lead to the FSGS lesions. Our study is a strong example of a bench-to-bed scientific project and will have direct impact on the patients. Our results will facilitate development of novel treatment strategies for currently incurable form of FSGS and should allow us to use optimal strategy for individual patients in order to save their kidneys and improve their quality of life.